On-the-ground application of the 'temporary recommendation for use' regulatory measure on off-label use of baclofen for alcohol dependence in France: a regional survey of community pharmacies.

The 'temporary recommendation for use' (TRU) is a French novel regulatory measure for off-label drug. The first TRU to be issued by the French drug agency (in March 2014) pertained to the off-label use of baclofen for alcohol dependence (AD). We performed a questionnaire-based survey of the on-the-ground application of the baclofen TRU among community pharmacies in northern France. A pharmacist from 70 of the 219 pharmacies contacted (response rate: 32.0%) completed the questionnaire. The mean ± standard deviation number of off-label baclofen prescriptions for AD was 2.3 ± 2.2 per pharmacy per month. 65.2% of these prescriptions were issued by primary care physicians. 65.7% of the pharmacists had never seen 'TRU' written on the prescription, and 80.3% delivered a prescription without checking whether the patient had been included by the prescriber in the TRU. The main criterion used to identify off-label prescribing was the patient's medical history (according to 74.6% of pharmacists) and the prescription of an above-threshold dose (73.1%). 87.1% of the pharmacists were aware of the baclofen TRU, and 42.9% had actually read the document. 17.9% of the pharmacists estimated that the TRU had changed their attitude to off-label baclofen prescription, and 29.9% (20 out of 67) of them wanted to be more involved in the TRU process. Community pharmacists were well informed about the off-label use of baclofen for AD and the TRU. However, a majority of baclofen prescribers did not fulfill the TRU requirements while a majority of pharmacists did not exert any control over these off-label prescriptions. In practice, in 2015 the TRU measure had thus a limited impact on both the baclofen prescribing and delivery practices.

Safety reports on the off-label use of baclofen for alcohol-dependence: recommendations to improve causality assessment.

INTRODUCTION: The off-label use of high-dose baclofen (HDB) for alcohol-dependence has recently spread. However, HDB has been associated with numerous reports of adverse events (AEs). Pharmacovigilance reporting is supposed to differentiate AEs from adverse drug reactions (ADRs), for which the causality of the drug is determined using validated methods. AREAS COVERED: Since 2010, we found 20 publications on baclofen-related AEs in alcohol dependence, in Medline-referenced journals or national pharmacovigilance reports. We focused on whether these reports used causality algorithms, and provided essential elements for determining baclofen causality and excluding the involvement of alcohol and other psychoactive substances or psychotropic drugs. In half of the cases, no causality algorithm was used. Detailed information on baclofen dosing was found in 17 out of 20 (85%) articles, whereas alcohol doses were given only in 10 (50%) publications. Other psychoactive substances and psychotropic drugs were broached in 14 (70%) publications. EXPERT OPINION: future publications reporting suspected HDB-induced ADRs should use validated causality algorithms and provide sufficient amount of contextual information for excluding other potential causes. For HDB, the psychiatric history, and the longitudinal description of alcohol consumptions and associated doses of psychoactive substances or psychotropic medications should be detailed for every reported case.

Sexual dysfunction induced by intrathecal baclofen administration: is this the price to pay for severe spasticity management?

INTRODUCTION: Intrathecal administration of baclofen (ITB) is widely recognized as an effective treatment for severe spasticity of both spinal and supraspinal origin with fewer side effects. The lower drug dosages used for spinal intrathecal administration, acting directly on the receptor sites, result in greater therapeutic efficacy with less systemic toxicity than with oral preparations. AIM: This study aims to prospectively evaluate the effects of ITB on erectile function in male patients affected by severe spasticity. METHODS: Twenty adult male patients, with a 34.85 ± 10.27 mean age, affected by severe spasticity mainly due to spinal cord lesions (10 traumatic, three vascular, six degenerative, and one congenital in origin) and treated with ITB, were enrolled in the study. All participants underwent specific clinical scales to evaluate force, muscle tone, cognition and mood, and specific sexual questionnaires, including an accurate semi-structured interview. MAIN OUTCOME MEASURE: The International Index of Erectile Function (IIEF) was used to evaluate sexual function before and after pump implantation. RESULTS: A comparative analysis of the neurological scales and psychometric scores at T1 (baseline) and T2 (follow-up) showed statistically significant differences before and after pump implantation. In particular, we noted a significant decrease in the IIEF median scores (from 0.42 ± 0.07 to 0.14 ± 0.02, P value < 0.0001) and a correlation between ITB dosage and IIEF scores (ρ = -0.60; P < 0.05). CONCLUSIONS: This study supports previous findings on a possible negative effect of ITB on sexual function, with regard to erection. Patients who are considering ITB for treatment of severe spasticity should be informed about possible but reversible sexual side effects, especially at higher dosage. Future studies with larger samples should be fostered to confirm these findings for a better management of these, often young, patients.

Intrathecal baclofen in multiple sclerosis: too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.

[A system of prescriptions without drug approval: example of baclofen]. / Un dispositif de prescriptions hors-AMM : exemple du baclofène.

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies.

The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study.

The surge in dopamine in ventral striatal regions in response to drugs of abuse and drug-associated stimuli is a final common pathway of addiction processes. GABA B agonists exert their effects indirectly, by quieting dopaminergic afferents. The ability of the GABA B agonist, baclofen to ameliorate nicotine and drug motivated behavior is established within the animal literature, however its potential to do so in humans is understudied, particularly with respect to its possible utility as a smoking cessation agent. We conducted a nine-week double-blind placebo-controlled pilot trial of baclofen for smoking reduction (N=30/group) in smokers contemplating, but not quite ready to quit. Baclofen was titrated upwards to 20mg q.i.d. over a period of twelve days. The primary outcome measure was the number of cigarettes smoked per day (CPD). A significant group by time effect of medication was observed. Baclofen was superior to placebo in reducing CPD (beta=0.01, t=1.97, p<0.05). The most common side effect reported during baclofen treatment is transient drowsiness, however there were no differences between groups in mild, moderate, or severe sedation. Craving was significantly lowered at end of treatment in all smokers (p<0.02). Retention did not differ between groups. In line with a multitude of preclinical studies examining the effects of baclofen on drug-motivated behavior, baclofen reduced CPD. In agreement with other studies examining craving and drug use, reductions in CPD were accompanied by a reduction in craving, a major motivator underlying continued smoking and relapse. These preliminary results demonstrate provisional evidence of the utility of baclofen to aid in smoking cessation and indicate further investigation.

The incidence and management of tolerance in intrathecal baclofen therapy.

STUDY DESIGN: Retrospective study. OBJECTIVES: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. METHODS: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. RESULTS: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (P<0.05), and then stabilized around a mean dose of 350 microg per day. Eight patients (22%) developed tolerance, defined as a dose increase of >100 microg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance. Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n=11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pump-related complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. CONCLUSIONS: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.

Intrathecal baclofen therapy: challenges in patients with multiple sclerosis.

Intrathecal baclofen (ITB) is a recognized therapy for severe spasticity of both spinal and cerebral origin, with documented positive clinical outcomes for many patients with multiple sclerosis (MS). This article reviews some specific considerations concerning the use of ITB in the MS population, based on the author's 10 years of clinical experience. The unpredictable and progressive nature of the disease affects the identification of appropriate goals, the patient's decision-making process, and the evaluation of the response to the treatment over time. Patients with MS may be more sensitive to intrathecal baclofen than patients with other diagnoses, and may need a lower dose for both the screening test and maintenance therapy. Subtle cognitive changes may affect the patient's ability to understand the education needed for successful management of ITB. Some practical strategies are offered for the nurse involved in the care of these patients in each stage of the therapy.

A benefit-risk assessment of baclofen in severe spinal spasticity.

Baclofen is used for treatment of the spasticity of spinal origin that is a common sequela of spinal cord injury and multiple sclerosis; spasticity occurs in about 50% of patients affected by these disorders. In open-label studies of oral baclofen, the drug improved spasticity in 70-87% of patients; additionally, improvement in spasms was reported in 75-96% of patients. In double-blind, crossover, placebo-controlled trials, baclofen was reported to be effective, producing statistically significant improvements in spasticity. Tizanidine is the antispasticity drug that has been most widely compared with oral baclofen; studies have generally found the two drugs to have equivalent efficacy. However, tizanidine has better tolerability, in particular weakness was reported to be occur less frequently with tizanidine than with baclofen. The main adverse effects of oral baclofen include: sedation or somnolence, excessive weakness, vertigo and psychological disturbances. The incidence of adverse effects is reported to range from 10% to 75%. The majority of adverse effects are not severe; most are dose related, transient and/or reversible. The main risks of oral baclofen administration are related to withdrawal: seizures, psychic symptoms and hyperthermia can occur. These symptoms improve after the reintroduction of baclofen, usually without sequelae. When not related to withdrawal; these symptoms mainly present in patients with brain damage and in the elderly. The limited data on baclofen toxicity in patients with renal disease suggest that administration of the drug in these persons may carry an unnecessarily high risk. Intrathecal baclofen is indicated for use in patients with spasticity of spinal origin unresponsive to treatment with maximum doses of oral baclofen, tizanidine and/or dantrolene. The benefits of continuous intrathecal baclofen infusion have been demonstrated: >80% and >65% of patients have improvement in tone and spasms, respectively. The main risks of intrathecal baclofen infusion are symptoms related to overdose or withdrawal; the latter is more important because of the associated severe effects on clinical status and the possibility of death, but it is responsive to rapid treatment. Overdose primarily arises from drug test doses or human error during refill and programming of the pump, and withdrawal most commonly occurs as a result of a problem with the delivery system. Since the adverse consequences do not exceed the benefits of oral and intrathecal baclofen for patients with spinal spasticity, the benefit/risk assessment is favourable.

Functional assessment following intrathecal baclofen therapy in children with spastic cerebral palsy.

The purpose of this article is to describe outcomes of intrathecal baclofen therapy for 29 patients with cerebral palsy, focusing on impairments, functional limitations, and disability. Patients received individualized rehabilitation and were followed up to 24 months. The primary outcome measures were the Ashworth Scale and the functional skills and caregiver assistance scales of the Pediatric Evaluation of Disability Inventory (PEDI). Ashworth Scale scores were significantly reduced (P < or = .0005). All areas of functional skills and caregiver assistance improved. Comparing groups of adults and patients less than 18 years, there were no significant differences, but there was a relationship between age and dose. Comparing groups of patients in high and low levels of independent functional mobility, no significant differences were found. These results provide suggestive evidence that the combination of intrathecal baclofen therapy and rehabilitation has positive effects across the dimensions of disablement. This study serves as a basis for high-level scientific studies of these effects.